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Potassium Carbonate → N-(4-(3-(1-(cyanomethyl)-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-1-(4-Fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

HRID 1046027
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HRID 1046027 반응식
Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]2[C:20](=[O:32])[N:21]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=[CH:23][CH:24]=2)=[O:18])=[C:11]([F:33])[CH:10]=1.CC1(C)C(C)(C)OB([C:42]2[CH:43]=[N:44][N:45]([CH2:47][C:48]#[N:49])[CH:46]=2)O1.C(=O)([O-])[O-].[K+].[K+].C([O-])(O)=O.[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:48]([CH2:47][N:45]1[CH:46]=[C:42]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3[C:20](=[O:32])[N:21]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[CH:22]=[CH:23][CH:24]=3)=[O:18])=[C:11]([F:33])[CH:10]=2)[CH:43]=[N:44]1)#[N:49]
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참가 물질

8

반응물 4

HCID 11430Potassium CarbonateHCID 516892Sodium BicarbonateHCID 674680952-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetonitrileHCID 68009215N-(4-(3-Bromopyridin-4-yloxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

생성물 1

HCID 54596485
N-(4-(3-(1-(cyanomethyl)-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-1-(4-Fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide
수율 24%

시약·촉매·용매 3

HCID 178418397HCID 178418397, 화합물촉매HCID 962Water용매HCID 312751,4-Dioxane용매

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온도
85 °C

실험 절차

N-(4-(3-Bromopyridin-4-yloxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.119 g, 0.231 mmol) was combined with 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetonitrile (0.054 g, 0.231 mmol) and potassium carbonate (0.096 g, 0.692 mmol) in dioxane (4 mL) and water (0.667 mL), sparged with argon for several minutes, treated with tetrakis(triphenylphosphine)palladium(0) (0.013 g, 0.012 mmol) and heated to 85° C. overnight. The mixture was cooled to room temperature, treated with saturated NaHCO3 and extracted with EtOAc (2×). The combined organics were washed with brine, dried over MgSO4 and concentrated to dryness. The crude material was purified over silica gel (40-100% EtOAc/Hex) to afford N-(4-(3-(1-(cyanomethyl)-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-1-(4-Fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (30 mg, 24% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.45 (s, 1H); 8.91 (s, 1H); 8.61 (dd, J=7.4, 2.1 Hz, 1H); 8.55 (m, 1H); 8.44 (s, 1H); 8.29 (d, J=5.7 Hz, 1H); 8.24 (s, 1H); 8.16 (dd, J=6.6, 2.2 Hz, 1H); 7.67 (dd, J=11.0, 7.3 Hz, 1H); 7.60 (dd, J=8.7, 4.9 Hz, 2H); 7.42 (t, J=8.7 Hz, 2H); 6.75 (m, 2H); 5.54 (s, 2H); MS (ESI) m/z: 543.1 (M+H+).

후처리

  1. customsparged with argon for several minutes
  2. temperatureThe mixture was cooled to room temperature
  3. extractionextracted with EtOAc (2×)
  4. washThe combined organics were washed with brine
  5. dry with materialdried over MgSO4
  6. concentrationconcentrated to dryness
  7. customThe crude material was purified over silica gel (40-100% EtOAc/Hex)

출처 및 근거

ORD 기록
ord-4ba2631ab75a45cc97013670e4928e29
출처 데이터셋
uspto-grants-2013_10
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US08569319B2

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